The present invention relates to polymers formed from radical polymerization of ethylenically unsaturated monomers including an ammonium phosphate ester zwitterionic monomer, and processes for producing them. In particular, the invention relates to emulsion polymerization processes for forming high solids emulsions without the incorporation of non-polymerisable emulsifier, and to the use of these emulsions to biocompatibilise substrates.
Yamaguchi et al in Makromol. Chem. (1989), 190, 1195-1205, describe an oil-in-water emulsion polymerization of styrene in the presence of polymerisable and non-polymerisable phosphoryl choline compounds as emulsifier. The latex product is stable, the non-polymerisable emulsifiers giving more regular shaped and sized spherical particles than the polymerisable emulsifiers. The polymerizations were conducted to form latexes having around 10 wt % solids. The mole percent of polymerisable emulsifier based on total monomer is around 10%. The base monomer on which the polymerizations were based was styrene.
Sugiyama et al in Polym. J. (1993) 25(5), 521-527, describe an emulsifier free radical polymerization of ethylenically unsaturated monomers comprising methylmethacrylate, in the presence of an ethylenically unsaturated ammonium phosphate ester zwitterionic monomer, using a water-soluble initiator. The latex product had a concentration of around 10% by weight polymer. Increasing the amount of zwitterionic monomer resulted in reduced stability of the latex. Whilst low levels of zwitterionic monomer reduced the particle size of microspheres in the latex product as compared to a process containing no such monomer, increasing the level from a mole % of 0.01, based on total monomer, to 0.5 resulted in an increase in the diameter of the microsphere of the product. The microspheres themselves were found to have low levels of adsorption of albumin as compared to polymethylmethacrylate polymerised in the absence of the ammonium phosphate ester zwitterionic monomer.
Sugiyama et al, in J. Polym. Sci., Part A (1997) 35, 3349-3357, describe oil-in-water emulsion polymerization of methylmethacrylate, optionally with a comonomer of hydroxypropyl methacrylamide, in the presence of 2-methacryloyloxyethyl-2xe2x80x2-trimethylammoniumethyl phosphate inner salt (MPC). The MPC is present at a level of about 1% based on total ethylenically unsaturated monomer. The latex product had a polymer solids concentration of around 10% by weight. Again the presence of MPC resulted in a decrease in the stability of the latex product with more aggregates being formed. The process was dependent on the choice of initiator, between potassium peroxodisulphate, and 2,2xe2x80x2-azobis[2-(imidazolin-2-yl)propane]dihydrochloride (ABIP). The ABIP initiated products were more influenced by the presence of the MPC monomer in terms of particle size and level of aggregates. In both Sugiyama papers, the reaction mixture was agitated at high speed, with all monomers being included in the reaction vessel at the commencement of the polymerization. It is not clear how the methylmethacrylate dispersed phase is maintained in suspension during the process for example with no MPC monomer.
Zimehl et al, in Colloid Polym. Sci. (1990) 268, 924-933 describe emulsion polymerization of polystyrene using potassium peroxodisulphate in the presence of N-(3-sulphopropyl)-N-methacrylomidyl propyl (N,N-dimethylammonium betaine) (SPP) at SPP concentrations in the range 5 to 70% by weight based on total monomer. The particle size of the latex product was dependent upon the initiator and the level of betaine comonomer. Again, all of the monomers were dispersed into the aqueous continuous phase before polymerization was initiated. The solids concentration of product latex was around 10% by weight.
In U.S. Pat. No. 3,497,482 Hwa et al describe a copolymerization of N,N-dimethyl-N-(2-methacryloyloxyethyl)-N-(3-sulphopropyl ammonium inner salt) (SPE), with ethyl methacrylate and acrylamide, in an aqueous continuous phase. Hwa produces a metastable oil-in-water product. He does not describe the particle size of the latex.
In WO-A-93/01221 we describe a range of copolymers of zwitterionic monomer with comonomers such as hydrophobic comonomers, ionic comonomers or reactive comonomers. The copolymers are formed by co-dissolving all the monomers into a solvent in which monomers and polymer are soluble and recovered by precipitation techniques. It is suggested that the product might be a micro emulsion but no examples of emulsion polymerization are given. The polymers are used to coat substrates in order to improve their biocompatibility. Whilst improvements in biocompatibility may be achieved by using molar percentages of 1% or lower of zwitterionic monomer, based on total ethylenically unsaturated monomer, it is often found that at least 20 mol % zwitterionic monomer is needed for satisfactory levels of improved biocompatibility. The higher the level of zwitterionic monomers, the greater the expense.
Zwitterionic polymers made by the techniques such as are described in WO-A-93/01221, may be blended with physically or mechanically desirable copolymers to provide blends which have good biocompatibilising properties. The level of zwitterionic monomer in the total blend is reduced, thereby rendering the product more cost effective than single component zwitterionic polymer products. Such blends are described in, for instance, WO-A1-94/14897 and PCT/GB00103985 (unpublished at the priority date of this application). PCT/GB00/03985 describes blends of MPG copolymers with higher alkyl methacrylate comonomers, blended with alkyl(meth)acrylate polymers. Such blends, co-dissolved in a suitable organic solvent may be coated onto a surface to form a coating having micro-domains of relatively hydrophilic and relatively hydrophobic character. The blends may express higher levels of phosphorylcholine groups at the surface than in the bulk of the coating. This should allow the properties of a substrate coated with the polymer to be tailored for particular biocompatibility.
It would be desirable to produce a latex having high solids, in which a zwitterionic monomer is one of the ethylenically unsaturated monomers. It would furthermore be desirable to produce a copolymer of an ammonium phosphate ester zwitterionic monomer including low levels of that monomer. It would be desirable to carry out an emulsion polymerization to produce a stable latex product having a small particle size, and low particle size distribution and which forms coatings having desirable biocompatibilising properties without using high levels of ammonium phosphate ester zwitterionic monomer.
In a new emulsion polymerization process according to the invention, a mixture of ethylenically unsaturated monomers including water-insoluble monomers is polymerised in the dispersed phase of an oil-in-water emulsion in the presence of a water-soluble radical initiator, ethylenically unsaturated monomers including an ammonium phosphate ester zwitterionic monomer the process being characterised by being carried out at component concentrations to give a latex product having a polymer solids concentration of at least 20% by weight.
In the new process, the solids concentration of the product is usually no more than 60%, preferably in the range 25 to 50% by weight.
The process of the invention may be carried out in the presence of non-polymerisable emulsifiers and/or stabilisers. It is found that it is possible for the emulsion and latex product to be adequately stabilised by the presence of the ammonium phosphate ester zwitterionic monomer, optionally in combination with other surface active monomers. The process is preferably carried out therefore in the substantial absence of non-polymerisable surfactant/emulsifier and stabiliser.
The ammonium phosphate ester zwitterionic monomer is preferably included in an amount in the range 0.01 to 5% by weight, based on the total weight of monomers. More preferably the level of the zwitterionic monomer is in the range 0.05 to 2% by weight, for instance 0.1 to 1% by weight.
The zwitterionic monomer preferably has the general formula I
YBX xe2x80x83xe2x80x83I
in which
X is the ammonium phosphate ester zwitterionic group;
B is a bond, or a straight branched alkanediyl, alkylene oxaalkylene, or alkylene (oligooxalkylene) group, optionally containing one or more fluorine substituents; and
Y is an ethylenically unsaturated group selected from H2Cxe2x95x90CRxe2x80x94COxe2x80x94Axe2x80x94, H2Cxe2x95x90CRxe2x80x94C6H4xe2x80x94A1xe2x80x94, H2Cxe2x95x90CRxe2x80x94CH2A2xe2x80x94, R2Oxe2x80x94COxe2x80x94CRxe2x95x90CRxe2x80x94COxe2x80x94Oxe2x80x94, RCHxe2x95x90CHxe2x80x94COxe2x80x94Oxe2x80x94, RCHxe2x95x90C(COOR2)CH2xe2x80x94COxe2x80x94Oxe2x80x94, 
A is xe2x80x94Oxe2x80x94 or NR1;
A1 is selected from a bond, (CH2)nA2 and (CH2)nSO3xe2x80x94 in which n is 1 to 12;
A2 is selected from a bond, xe2x80x94Oxe2x80x94, Oxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94O, xe2x80x94COxe2x80x94NR1xe2x80x94, xe2x80x94NR1xe2x80x94CO, xe2x80x94Oxe2x80x94COxe2x80x94NR1xe2x80x94, and xe2x80x94NR1xe2x80x94COxe2x80x94Oxe2x80x94;
R is hydrogen or C1-4 alkyl;
R1 is hydrogen, C1-4 alkyl or BX; and
R2 is hydrogen or C1-4 alkyl.
Generally in the zwitterionic group X, the anion is closer to B than the cation. However in some zwitterions, the cation is closer to the group B than is the anion (called hereinafter phosphobetaines).
Preferably X is a group of the general formula II 
in which R3 is alkanediyl of 1 or more, preferably 2-6 carbon atoms optionally containing one or more ethylenically unsaturated double or triple bonds, disubstituted-aryl (arylene), alkylene arylene, arylene alkylene, or alkylene aryl alkylene, cycloalkanediyl, alkylene cycloalkyl, cycloalkyl alkylene or alkylene cycloalkyl alkylene, and optionally contains one or more fluorine substituents and/or one or more functional groups; and
either the groups R4 are the same or different and each is hydrogen or alkyl of 1 to 4 carbon atoms, preferably methyl, or aryl, such as phenyl, or two of the groups R4 together with the nitrogen atom to which they are attached form an aliphatic heterocyclic ring containing from 5 to 7 atoms, or the three groups R4 together with the nitrogen atom to which they are attached form a fused ring structure containing from 5 to 7 atoms in each ring, and optionally one or more of the groups R4 is substituted by a hydrophilic functional group.
Alternatively X may be a group of the general formula III 
in which the group R5 are the same or different and each is hydrogen, C1-4 alkyl, such as methyl, or aryl, such as phenyl;
R6 alkanediyl of 1 or more, preferably 2-6 carbon atoms optionally containing one or more ethylenically unsaturated double or triple bonds, disubstituted-aryl (arylene), alkylene arylene, arylene alkylene, or alkylene aryl alkylene, cycloalkanediyl, alkylene cycloalkyl, cycloalkyl alkylene or alkylene cycloalkyl alkylene, optionally contains one or more fluorine substituents and/or one or more functional groups;
R7 is hydrogen, or an optionally substituted C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C6-24 aryl or C7-24 aralkyl group.
In a group of the general formula III, R7 is preferably other than hydrogen and is more preferably an unsubstituted C1-6 alkyl, C6-12 aryl or C7-12 aralkyl group. Any substituents in a substituted group R7 are usually fluorine atoms, or hydroxyl or C1-4 alkoxy groups.
In the new emulsion polymerization process the monomers preferably include at least 50% by weight of ethylenically unsaturated polymerisable monomers. Examples of suitable monomers are compounds selected from the group consisting of C1-12-alkyl(alk)acrylates, C2-12-alkyl- and -dialkyl-(alk)acrylamides, water insoluble vinyl esters or ethers, allylic compounds, maleic or fumaric esters or imides, aconitic compounds, styrenic compounds, e.g. styrene, and mixtures thereof.
As is known in emulsion polymerization techniques, the choice of monomers affects the physical properties of the mixture, in particular whether the polymer particles of the product are able to coalesce after removal of water, for instance to form stable film coatings. It is preferred that the hydrophobic compounds are selected for their ability to form films at suitable temperatures for coating processes.
It is found that particularly desirable characteristics are achieved by using a blend of hydrophobic compounds, which would tend to confer different properties of hardness on the resultant polymer. Monomers which tend to produce hard polymers are lower alkyl(meth)acrylate especially methylmethacrylate. Compounds which tend to produce softer copolymers are alkylacrylates and methacrylates having straight or branched alkyl groups with at least 4 carbon atoms, such as butyl, hexyl, 2-ethylhexyl or n-octyl groups. Preferably the hydrophobic compound comprises a mixture of methylmethacrylate with a C4-8 alkyl acrylate.
The emulsion polymerization itself and the properties of the product, especially the biocompatibility of films produced from the emulsion, are beneficially affected by incorporating a zwitterionic comonomer. The zwitterionic comonomer preferably comprises as cation a quaternary ammonium or phosphonium group but may comprise a tertiary sulphonium group. The anion may be a sulphonate, sulphate, phosphonate, or carboxylate anion, most preferably a sulphonate or carboxylate anion. Most preferably the comonomer is a sulpho- or carboxy-betaine monomer. The zwitterionic comonomer is suitably a compound of the general formula IV
Y1B1X1 xe2x80x83xe2x80x83IV
in which
Y1 is an ethylenically unsaturated group selected from H2Cxe2x95x90CR8xe2x80x94COxe2x80x94A6xe2x80x94, H2Cxe2x95x90CR8xe2x80x94C6H4xe2x80x94A3xe2x80x94, H2Cxe2x95x90CR8xe2x80x94CH2A4xe2x80x94, R9Oxe2x80x94COxe2x80x94CR8xe2x95x90CR8xe2x80x94COxe2x80x94Oxe2x80x94, R8CHxe2x95x90CHxe2x80x94COxe2x80x94Oxe2x80x94, R8CHxe2x95x90C(COOR9)CH2xe2x80x94COxe2x80x94O, 
A6 is xe2x80x94Oxe2x80x94 or NR10;
A3 is selected from a bond, (CH2)mA4 and (CH2)mSO3xe2x80x94 in which m is 1 to 12;
A4 is selected from a bond, xe2x80x94Oxe2x80x94, Oxe2x80x94COxe2x80x94, COxe2x80x94O, xe2x80x94COxe2x80x94NR10xe2x80x94, xe2x80x94NR10xe2x80x94CO, xe2x80x94Oxe2x80x94COxe2x80x94NR10xe2x80x94, and NR10xe2x80x94COxe2x80x94Oxe2x80x94;
R8 is hydrogen or C1-4 alkyl;
R10 is hydrogen, C1-4-alkyl or B1X1;
R9 is hydrogen or C1-4 alkyl;
B1 is a bond, or a straight branched alkanediyl, alkylene oxaalkylene, or alkylene (oligooxalkylene) group, optionally containing one or more fluorine substituents; and
X1 is a zwitterionic group other than an ammonium phosphate ester.
The zwitterionic group X1 may have, as anion a carboxylate group, a sulphate group, a sulphonate group or a phosphonate group, preferably carboxylate or, more preferably a sulphonate group. The zwitterionic group X1 may have as cationic group an ammonium, phosphonium or sulphonium group, preferably an ammonium group.
A preferred zwitterionic group X1 has the general formula V 
where the groups R11 are the same or different and each is hydrogen or C1-4 alkyl and s is from 2 to 4. Preferably the groups R11 are the same. It is also preferable that at least one of the groups R11 is methyl, and more preferable that the groups R11 are both methyl. Preferably s is 2 or 3, more preferably 3.
Alternatively the zwitterionic group may be an amino acid moiety in which the alpha carbon atom (to which an amine group and the carboxylic acid group are attached) is joined through a linker group to the backbone of the biocompatible polymer. Such groups may be represented by the general formula VI 
in which
A5 is a valence bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94or xe2x80x94NHxe2x80x94, preferably xe2x80x94Oxe2x80x94,
R12 is a valence bond (optionally together with A5) or alkanediyl, xe2x80x94C(O)alkylene-, NHCOalkylene or xe2x80x94C(O)NHalkylene, preferably alkanediyl and preferably containing from 1 to 6 carbon atoms; and
the groups R13 are the same or different and each is hydrogen or alkyl of 1 to 4 carbon atoms, preferably methyl, or two or three of the groups R13, together with the nitrogen to which they are attached, form a heterocyclic ring of from 5 to 7 atoms, or the three group R13 together with the nitrogen atom to which they are attached form a fused ring heterocyclic structure containing from 5 to 7 atoms in each ring.
Alternatively the zwitterion may be a carboxy betaine xe2x80x94N⊕(R14)2(CH2)rCOOxe2x8ax96 in which the R14 groups are the same or different and each is hydrogen or C14 alkyl and r is 2 to 6, preferably 2 or 3.
In another embodiment, the zwitterionic group X1 has the general formula VII 
W is S, PR16 or NR16;
the or each groups R16 is hydrogen or alkyl of 1 to 4 carbon atoms or the two groups R16 together with the heteroatom to which they are attached form a heterocyclic ring of 5 to 7 atoms;
R17 is alkanediyl of 1 to 20, preferably 1 to 10, more preferably 1 to 6 carbon atoms;
A7 is a bond, NH, S or O, preferably O; and
R18 is a C1-12 alkyl, C7-18 aralkyl or C6-18 aryl group or, where A7 is other than a bond, is a C1-12-alkoxy, C6-18-aryloxy or C7-18-aralkoxy group.
In compounds comprising a group of the general formula VII, it is preferred that
W is NR16;
each R16 is C1-4 alkyl; and
R17 is C2-6 alkanediyl.
In all embodiments, in the zwitterionic comonomer of the general formula IV Y1 is preferably H2Cxe2x95x90CR8xe2x80x94COxe2x80x94A3 xe2x80x94. Such acrylic moieties are preferably methacrylic, that is in which R8 is methyl, or acrylic, in which R8 is hydrogen. Whilst the compounds may be acrylamido compounds (in which A is NR10), in which case R10 is preferably hydrogen, or less preferably, methyl, most preferably the compounds are esters, that is in which A3 is O. Suitable examples of comonomer of the general formula IV are SPP and SPE.
In monomers of the general formula IV, especially where Y is the preferred acrylic group, B1 is most preferably an alkanediyl group. Whilst some of the hydrogen atoms of such group may be substituted by fluorine atoms, preferably B1 is an unsubstituted alkanediyl group, most preferably a straight chain group having 2 to 6 carbon atoms.
Where a zwitterionic comonomer is included, the ratio of that comonomer to ammonium phosphate ester zwitterionic monomer is preferably in the range (1 to 50):1, more preferably in the range (5 to 20):1.
The ethylenically unsaturated monomers may further comprise hydrophilic monomer, for instance relatively water-soluble monomers.
Hydrophilic monomers are preferably selected from the group consisting of C1-4-hydroxyalkyl(meth)acrylates, C1-4-hydroxyalkyl(meth)acrylamides, C1-3-alkoxy-C2-4-alkyl(meth)acrylates, C1-3-alkoxy-C2-4-alkyl(meth)acrylamides, C1-3-alkoxy-oligoethoxy(meth)acrylates, C1-4-dihydroxyalkyl(meth)acrylates, N-mono- or N,N- di- C1-2 alkyl (meth)acrylamides, N-vinylactams, and C2-4-hydroxyalkyl-oligoethoxy(meth)acrylates and mixtures thereof.
It has been found to be particularly useful to include, as a hydrophilic monomer, a monomer comprising an oligoethoxy moiety, that is selected from C1-3-alkoxy-oligoethoxy(meth)acrylates and C2-4-hydroxyalkyl-oligoethoxy(meth)acrylates, more preferably the alkoxy terminated compounds. Preferably an alkoxy group is methoxy or ethoxy. Such compounds preferably have 5 to 50 ethoxy groups, for instance in the range 10 to 20 methoxy groups. Oligoethoxylated polymerisable compounds improve the stability of the emulsion during the process, as well as the latex product, and may confer desirable wetting characteristics on a product polymer as well as useful biocompatibility.
A hydrophilic monomer is preferably included in an amount in the range 0.1 to 50% by weight of total monomers, more preferably an amount in the range 1 to 25% by weight, for instance an amount in the range 5 to 20% by weight. An oligo ethoxylated comonomer is preferably included in an amount in the range 1 to 20% by weight, more preferably in the range 5 to 10% by weight. It is often used in conjunction with one or more other hydrophilic monomers, such that the total amount of hydrophilic monomer is in the range 5 to 50% by weight.
The stability of the emulsion during polymerization is found to be improved if the pH of the emulsion is maintained slightly acidic, that is has a pH less than 7, more preferably in the range 4 to 6.8, for instance about 5. Whilst the acidity may be achieved by adding a non-polymerisable acid for instance a mineral acid, to the emulsion, it is preferable to include a polymerisable acid as one of the ethylenically unsaturated monomers. Preferably an ethylenically unsaturated acid is selected from fumaric acid, maleic acid, vinyl sulphonic acid and styrene sulphonic acid, more preferably selected from acrylic and methacrylic acids, and is most preferably methacrylic acid.
Where acidic monomer is included, it is present in an amount in the range 0.1 to 5% by weight, more preferably in the range 0.2 to 2% by weight, based on the total weight of monomers.
Other compounds, especially other monomers may be included in the polymerization mixture, for instance to achieve desired product characteristics.
It may also be desirable to include non-polymerisable components in the polymerization mixture, for instance in the continuous aqueous phase or in the dispersed oil phase, or at the interface. Non-polymerisable emulsifiers and suspending agents may be included, but are preferably not included. Drugs, especially water-insoluble, oil-soluble drugs may be added whereby they may become absorbed in the latex particles of the product.
It may be desirable to include cationic monomer, in order to provide a product polymer having an overall cationic charge.
As described in our application number WO-A-93/01221 and WO-A-98/22516, the presence of cationic groups in a polymer may confer desirable binding properties either to underlying counterionically charged surfaces, or to anionic compounds which may be contacted with a surface coated with the polymer to achieve desirable results.
A cationic monomer is preferably a compound of the general formula VIII
Y2B2Q xe2x80x83xe2x80x83VIII
in which
Y2 is an ethylenically unsaturated group selected from H2Cxe2x95x90CR19xe2x80x94COxe2x80x94A8xe2x80x94, H2Cxe2x95x90CR19xe2x80x94C6H4xe2x80x94A9xe2x80x94, H2Cxe2x95x90CR19xe2x80x94CH2A10, R21Oxe2x80x94COxe2x80x94CR19xe2x95x90CR19xe2x80x94COxe2x80x94Oxe2x80x94, R19CHxe2x95x90CHxe2x80x94COxe2x80x94Oxe2x80x94, R19CHxe2x95x90C(COOR21)CH2xe2x80x94COxe2x80x94Oxe2x80x94, 
A8 is xe2x80x94Oxe2x80x94 or xe2x80x94NR20xe2x80x94;
A9 is selected from a bond, (CH2)qA10 and (CH2)qSO3xe2x80x94 in which q is 1 to 12;
A10 is selected from a bond, xe2x80x94Oxe2x80x94, Oxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94O, xe2x80x94COxe2x80x94NR20xe2x80x94, xe2x80x94NR20xe2x80x94CO, Oxe2x80x94COxe2x80x94NR20xe2x80x94, and NR20xe2x80x94COxe2x80x94Oxe2x80x94;
R19 is hydrogen or C1-4 alkyl;
R20 is hydrogen, C1-4 alkyl or BX.
R21 is hydrogen or C1-4 alkyl;
B2 is a bond, or a straight branched alkanediyl, alkylene oxaalkylene, or alkylene (oligooxalkylene) group, optionally containing one or more fluorine substituents; and
Q is xe2x80x94N⊕R223, xe2x80x94P⊕R233 or xe2x80x94S⊕R232 in which either the groups R22 are the same or different and each is hydrogen, alkyl of 1 to 6 carbon atoms, preferably methyl, C1-6 hydroxyalkyl, aryl, such as phenyl, or C7-12 aralkyl, or two of the groups R22 together with the nitrogen atom to which they are attached form an aliphatic heterocyclic ring containing from 5 to 7 atoms, or the three groups R22 together with the nitrogen atom to which they are attached form a fused ring structure containing from 5 to 7 atoms in each ring, and optionally one or more of the groups R3 is substituted by a hydrophilic functional group, and
the groups R23 are the same or different and each is R22 or a group OR22, where R22 is as defined above mutatis mutandis.
In the cationic monomer of the general formula VIII Q is preferably xe2x80x94N⊕R223, in which each R22 is a C1-4 alkyl group, preferably each R22 being methyl. The group Y2 is preferably an acrylic group, that is of the formula H2Cxe2x95x90CR19COA8. In such groups R19 is either hydrogen or methyl, preferably methyl, and A8 is preferably xe2x80x94Oxe2x80x94. B2 is preferably a C2-618 alkanediyl group, more preferably a C2-6 alkanediyl. Examples of suitable cationic monomers are 2-(N,N-dimethylamino)ethyl methacrylate methyl chloride or methyl sulphate salt, and 2-(N,N-dimethyl amino) ethyl acrylate methyl chloride or methyl sulphate salt.
A cationic monomer may be included in an amount in the range 0.1 to 25% by weight, more preferably an amount in the range 1 to 20% by weight, most preferably in an amount in the range 2 to 15% by weight.
Other monomers which may useful be included in the mixture include functional monomers, comprising reactive groups which are useful to provide attachment points for ligands or for underlying substrate surfaces having co-reactive functional groups, or to provide inter- or intra-molecular crosslinkability. Such functional groups may react with co-reactive groups derived from other functional monomers such as hydroxyl or amine group containing monomers.
Preferably a reactive monomer has the general formula IX
Y3B3Q1 xe2x80x83xe2x80x83IX
in which
Y3 is an ethylenically unsaturated group selected from H2Cxe2x95x90CR24xe2x80x94COxe2x80x94A11xe2x80x94, H2Cxe2x95x90CR24xe2x80x94C6H4xe2x80x94A12, H2Cxe2x95x90CR19xe2x80x94CH2A13, R26Oxe2x80x94COxe2x80x94CR24xe2x95x90CRxe2x80x94COxe2x80x94Oxe2x80x94, R24CHxe2x95x90CHxe2x80x94COxe2x80x94Oxe2x80x94, R24CHxe2x95x90C(COOR26)CH2xe2x80x94COxe2x80x94Oxe2x80x94, 
A11 is xe2x80x94Oxe2x80x94 or xe2x80x94NR25;
A12 is selected from a bond, (CH2)rA13 and (CH2)rSO3xe2x80x94 in which r is 1 to 12;
A13 is selected from a bond, xe2x80x94Oxe2x80x94, Oxe2x80x94COxe2x80x94, COxe2x80x94O, xe2x80x94COxe2x80x94NR25xe2x80x94, xe2x80x94NR25xe2x80x94CO, xe2x80x94Oxe2x80x94COxe2x80x94NR25, and NR25xe2x80x94COxe2x80x94Oxe2x80x94;
R24 is hydrogen or C1-4 alkyl;
R25 is hydrogen, C1-4-alkyl or B3Q1;
R26 is hydrogen or C1-4 alkyl;
B3 is a bond, or a straight branched alkanediyl, alkylene oxaalkylene, or alkylene (oligooxalkylene) group, optionally containing one or more fluorine substituents.
Q1 is a reactive group selected from the group consisting of aldehyde groups; silane and siloxane groups containing one or more substituents selected from halogen atoms and C1-4-alkoxy groups; hydroxyl; amino; carboxyl; epoxy; xe2x80x94CHOHCH2Hal (in which Hal is selected from chlorine, bromine and iodine atoms); succinimido; tosylate; triflate; imidazole carbonyl amino; optionally substituted triazine groups; cinnamyl; ethylenically and acetylenically unsaturated groups; acetoacetoxy; methylol; and chloroalkylsulphone groups; acetoxy; mesylate; carbonyl di(cycloalkyl carbodiimidoyl; and oximino.
Preferred groups Q1 are aldehyde, reactive silane and siloxane, amino, epoxy, CHOHCH2Hal (in which Hal is halogen), succimimido, tosylate, triflate, imidazolecarbonyl amino and optionally substituted triazine groups. Most preferably Q1 is a trialkoxy silyl group, such as a trimethoxysilyl group.
In the reactive monomer of the general formula IX the ethylenically unsaturated group Y3 is preferably and acrylic type group, that is a group H2Cxe2x95x90CR24A11xe2x80x94, R24 preferably being hydrogen or, most preferably, methyl and A11 preferably being xe2x80x94Oxe2x80x94. Preferred groups B3 are C2-18 alkanediyl, most preferably C2-6-alkanediyl.
The emulsion polymerization of the invention may be carried out in a single step, in which all of the monomers are dispersed into an aqueous continuous phase and agitation applied to form an emulsion having suitable sized droplets followed by initiation of polymerization. However, optimum particle size distribution is achieved if a two-step process is used, in a first step of which a seed polymer is formed, and in the second step the seeds are grown. In such a process, the seed monomers are dispersed into the aqueous phase and polymerization is initiated. To the seed polymer latex, the remaining monomers and additional initiator are added, so that polymerization is initiated at the seeds. Monomer travels from monomer droplets to the polymer seeds.
Preferably in a process involving a seed polymerization step, the monomers from which the seed polymer is formed comprise at least a portion of the ammonium phosphate ester zwitterionic monomer which is preferably added to the polymerization mixture in the form of an aqueous solution. The seed monomers must include at least a portion of the water-insoluble monomers. These monomers are dispersed into the aqueous continuous phase in the presence of the ammonium phosphate ester zwitterionic monomer whereby an emulsion of seed monomer is formed. Polymerization is initiated by radical initiator by a water-soluble initiator.
After seed polymerization has continued until the yield of polymer is at least 1% based on solids, seed growth emulsion polymerization step is then carried out by adding further monomer including at least a portion of the remaining water-insoluble monomer to the emulsion, along with further water-soluble initiator. It may be desirable for the polymer formed after the initial seed polymerization step to have a substantially constant composition. In this case, it is desirable for a water-immiscible liquid containing the water-insoluble monomers and other compatible comonomers and for this mixture to be added in a single addition step or continuously over an extended period to the aqueous reaction mixture. If any of the monomers selected components for the ethylenically unsaturated monomers are immiscible with the water-insoluble monomer blend, it may be desirable for the or all of the monomers of that type to be added separately to the polymerization mixture, for instance in the form of an aqueous solution.
It is preferred that the monomer blend be added over a period during which polymerization continues to the reaction mixture, and that polymerization be continued after all of the monomer has been added. During the monomer feed period, it is preferred for initiator to be continuously added to the reaction mixture. Preferably a portion of initiator is retained until after all of the monomer has been added to the mixture and is then included to minimise the level of residual unpolymerised monomer in the product.
It may be desirable for the polymerization to form a core-shell morphology. Such morphologies are generally achieved by carrying out the polymerization, generally after a seed polymerization step, in two or more phases. Generally the polymer formed in the two or more phases differs in terms of the monomers used and/or their ratios. Using such techniques it is possible to form a product latex in which the polymer particles have tailored characteristics with cores and shells of desired hardness, desired hydrophilicity or desired porosity. Such characteristics are achieved by selecting monomers according to their glass transition temperatures, hydrophilicities, or crosslinkability. To achieve a low porosity product, for instance, it may be desirable to incorporate di-, tri- or higher-functional ethylenically unsaturated monomers, or to include functional monomers which may be reacted with the same or different functional monomers during or after polymerization to provide intermolecular crosslinks.
Core/shell morphology may be achieved by changing the composition of monomers added to the polymerization mixture during the polymerization process. Thus monomers for forming the core should be added and polymerised in the mixture before addition of monomers for forming the shell.
In one particular embodiment of the process of the invention, a zwitterionic comonomer is included as part of the ethylenically unsaturated monomer and is added to the polymerization mixture as a component of the aqueous initiator composition, and is preferably added continuously over a monomer feed period during which water-insoluble monomer blend is separately added to the polymerization mixture. Preferably a monomer feed period is conducted for a period in the range 5 to 1200 minutes, most preferably in the range 30 to 240 minutes.
By the use of the ammonium phosphate ester zwitterionic monomer it has been found possible to conduct the emulsion polymerization under conditions such that high solid content latex products are formed. Thus the level of polymer in the latex product may be higher than 20% by weight, for instance up to 6%, preferably in the range 20 to 60% by weight, without adversely affecting the stability nor viscosity. Such latexes are convenient to handle. Whilst water may be evaporated from the product latex to achieve such high solids materials, or the polymer particles may be recovered by agglomeration or coagulation techniques and redissolved into water, preferably no such steps are carried out to achieve the 20 to 50% by weight solids latex. Alternatively the latex may be diluted before use or compounded with other ingredients compatible with its end use, such as water, other latices or coalescing aids. Coalescing aids may assist in the film formation of the final product, especially where the polymer is film forming at a higher temperature than room temperature. One suitable component is a latex preservative, for instance which inhibits bacterial growth or is a biocide or fungicide, suitably an alcohol such as benzyl alcohol.
It is believed that this is the first time that ammonium phosphate ester zwitterionic monomers have been used in emulsion polymerization processes including a seed polymer formation phase. According to a further aspect of the invention there is provided a seeded emulsion polymerization process in which a mixture of ethylenically unsaturated monomers including water-insoluble monomers and an ammonium phosphate ester zwitterionic monomer is copolymerised in the dispersed phase of an oil-in-water emulsion in the presence of a water-soluble radical initiator comprising the steps
i) providing an aqueous solution comprising at least a portion of the ammonium phosphate ester zwitterionic monomer and a portion of the initiator;
ii) forming a dispersed phase comprising a monomer seed composition comprising at least a portion of the water-insoluble monomers to form a seed emulsion;
iii) initiating polymerization of the seed emulsion whereby a seed latex is formed;
iv) providing a seed growth monomer mixture comprising the remaining water-insoluble monomers; and
v) adding the monomer cell mixture to the seed polymer latex and initiating polymerization of the monomers of the seed growth mixture in the dispersed seeds, to form a product polymer latex.
In the seeded emulsion polymerization process it is preferred that all of the ammonium phosphate ester zwitterionic monomer is present in the seed polymerization mixture.
Whilst the novel seeded polymerization process may be carried out to provide a relatively low solid product polymer latex of less than 20%, for instance in the range 2 to 20%, it is possible to carry out the process under conditions such that the product latex has a solid concentration in the range 20 to 60% by weight.
The seeded polymerization process allows formation of a product polymer latex having very low distribution of product particle size. The particle size may be controlled by the levels of seed monomer, initiator and seed growth monomer, as well as the choice of the type and amount of ammonium phosphate ester zwitterionic monomer, as well as other monomer components. Preferably the product latex has dispersed phase with average particle diameter of less than 1 xcexcm, more preferably less than 500 nm, most preferably in the range 100 to 400 nm. Preferably the polydispersity of particle size (number average over weight average diameter) is in the range 1.0 to 2.0.
It is preferred that the level of initiator for these low particle size distributions is in the range 0.001 to 0.5 weight % based on solids, preferably in the range 0.01 to 0.1 weight % . Preferably the ratio of weight of combined seed monomer to seed growth polymer is in the range 1:99 to 99:1, preferably in the range 1:50 to 1:10.
The seeded emulsion polymerization technique may be used to form a core-shell polymer product, using the techniques described above in connection with the first aspect of the invention. In such a process the seed growth monomers comprise two or more mixtures including a core mixture and a shell mixture, usually differing in terms of composition.
The seeded emulsion polymerization process has preferred components as described above in connection with the first aspect of the invention.
The polymer latex product of the first aspect of the invention forms a further aspect of the invention. A novel stable latex comprises a dispersion of polymer particles in aqueous continuous phase, having a polymer concentration in the range 20 to 60% by weight based on the total weight of the latex, an average particle diameter of less than 1 xcexcm, the polymer being formed from radical polymerised ethylenically unsaturated monomers comprising water-insoluble monomer and ammonium phosphate ester zwitterionic monomer.
The novel latex may further comprise additional components. For instance it may be desirable to add to the latex suspended particulate solids selected from organic and inorganic water-insoluble materials. Particularly preferred are suspended inorganic solids such as pigments, preferably having particle sizes less than 1 xcexcm. The latex may additionally comprise dissolved or miscible components for instance to improve the storage stability of the latex, or to provide additional properties for the product of the final dried film. For instance, drugs may be incorporated into the latex, either by adding a suspension or an aqueous or organic solvent-based solution to the latex. Colouring agents may also be included.
The novel latex, or the product of one of the novel polymerization processes, may be used as a coating composition.
According to a further aspect of the invention there is provided a novel coating process in which such a dispersion is coated onto a substrate to form a liquid coating on a surface thereof, and water is removed from the liquid coating to form a stable solid polymer coating on the said surface. Generally water is removed by evaporation although contact with precipitating solvents may also be utilised. Evaporation may be conducted at raised temperature and/or reduced pressure, and coalescing acids, such as alcohols, esters, glycols or other ethers, may be used to provide added control over film formation.
Preferably water removal is conducted under conditions of raised temperature under which the polymer particles coalesce to form a coherent and substantially void-free, preferably clear film.
The dried film may be subjected to additional steps such as curing, for instance by heating, especially where the monomers include a cross-linking monomer such as monomers of the general formula IX above. Gamma or other e.m. radiation or ethyleneoxide treatment may also be carried out to cure and/or sterilise the film.
The product films have particularly desirable biocompatibilising properties. They are generally used in environments in which the coated surface is contacted with aqueous liquids, generally biological liquids, for instance containing dissolved protein or suspended cells, such as bacterial or, preferably, blood cells. Preferably such liquids are selected from blood and serum.
According to a further aspect of the invention there is provided a novel biocompatibilising process in which a substrate is biocompatibilised by coating it with a latex according to the third aspect of the invention or which is the product of a process according to the first or second aspects of the invention, water is removed, to leave a stable coating of solid polymer on the surface.
Some of the monomer compositions used in the first and second aspects of the invention are believed to be novel in themselves. Whilst the novel emulsion polymerization techniques are believed to optimise the polymer properties, it is possible that other techniques may be suitable for copolymerising these monomers to form polymers having desirable characteristics. Such novel polymers are obtainable by radical polymerization of ethylenically unsaturated monomers comprising:
i) 0.1 to 25% by weight of an ammonium phosphate ester zwitterionic monomer;
ii) 0.1 to 25% by weight of a zwitterionic comonomer different to i); and
iii) 25 to 99% of a hydrophobic monomer.
Preferably this hydrophobic monomer is a compound as described above. Most preferably it is selected from the group consisting of C1-12-alkyl(alk)acrylates, C2-12-alkyl- and -dialkyl-(alk)acrylamides and styrene, and mixtures thereof.
The novel polymers may further comprise:
iv) 0.01 to 50% by weight hydrophilic monomer, preferably selected from the group consisting of C1-4-hydroxyalkyl(meth)acrylates, C1-4-hydroxyalkyl(meth)acrylamides, C1-3-alkoxy-C2-4-alkyl(meth)acrylates, C1-3-alkoxy-C2-4-alkyl(meth)acrylamides, C1-3-alkoxy-oligoethoxy(meth)acrylates, C1-4-dihydroxyalkyl(meth)acrylates, N-mono- or N,N- di- C1-2 alkyl (meth)acrylamides, N-vinylactams, and C2-4-hydroxyalkyl-oligoethoxy(meth)acrylates and mixtures thereof.
The hydrophilic monomer preferably comprises an oligoethoxylated compound, preferably in an amount in the range 0.1 to 10% by weight based on the total weight of monomer. Preferably such a monomer is selected from C1-3-alkoxy-oligoethoxy(meth)acrylates and C2-4-hydroxyalkyl-oligoethoxy(meth)acrylates, more preferably the alkoxy terminated compounds.
In one embodiment the novel polymer comprises 0.01 to 20% by weight, more preferably 0.1 to 5% by weight reactive monomer, comprising the general formula X defined above.
In another embodiment of the invention, the monomers include 0.01 to 10%, preferably 0.1 to 2% by weight anionic monomer, preferably selected from fumaric acid, maleic acid, vinyl sulphonic acid and styrene sulphonic acid, more preferably selected from acrylic and methacrylic acids, and is most preferably methacrylic acid.
In another embodiment of the polymer of the invention, the monomers include 1 to 25%, preferably 2 to 15% cationic monomer, preferably a compound of the general formula VIII defined above.
There is also provided in the present invention a film formed of the novel polymer. Preferably the film is a coherent, substantially void free film, preferably in the form of a coating on a surface of a substrate. The substrate is preferably the surface of a device for use in contact with biological fluids or organs, especially a device used in contact with aqueous liquids susceptible to fouling by proteins, carbohydrates, microbes or cells of higher organisms, cell culture substrates, assay devices, biosensors etc. Most preferably the substrate is the surface of a medical device, for instance an ophthalmic device such as a contact lens, a corneal onlay or an ophthalmic implant, or is a coating on a prosthesis, a guidewire, a catheter, a drug delivery implant, a stent, a vascular graft, a blood filter or extra corporeal circuitry components
In a drug delivery device, the active drug may be incorporated into the film by being a component of the coating latex, or by contacting the coated product, before or after curing, with a suitable drug to allow absorption or adsorption in or to the film.
The following examples illustrate the invention: